PROJECT SUMMARY This is a mentored patient-oriented career development award (K23) grant application. Dr. Wilson Gonsalves is a hematologist holding the position of Assistant Professor at Mayo Clinic. He has significant experience in multiple myeloma related clinical research and is seeking support for additional research time in a mentored setting to develop the skills necessary to transition into an independent translational researcher. His long-term goal is to develop an expertise in the cellular metabolism of clonal plasma cells in multiple myeloma. Mayo Clinic is an NCI-designated Comprehensive Cancer Center that fosters clinical care in an environment of translational research. Under the mentorship of Dr. Sreekumaran Nair, Dr. Shaji Kumar, and Dr. Taro Hitosugi, Dr. Gonsalves has developed a comprehensive career training plan that encompasses didactic training through various workshops and coursework in the use of stable isotopes, metabolomics, mass spectrometry, and bioinformatics. This didactic training will complement the practical experience he will gain from the completion of his proposed research project. He will also be advised by experts in metabolomics, biostatistics and bioinformatics. Multiple myeloma (MM) is a devastating clonal plasma cell malignancy responsible for over 12,000 deaths in the United States per year. Monoclonal gammopathy of undetermined significance (MGUS), a pre-malignant plasma cell disorder, always precedes MM. c-Myc is a known driver of progression of MGUS to MM but is also believed to promote glutamine anaplerosis into the tricarboxylic acid (TCA) cycle. Recent evidence has demonstrated the importance of glutamine addiction in clonal plasma cells of MM. Dr. Gonsalves' preliminary studies demonstrate the importance of glutamine anaplerosis in clonal plasma cells and the pathogenesis of MM. His research proposal will specifically determine if glutamine anaplerosis is higher in clonal plasma cells from MM compared to MGUS (Aim 1). It will also determine the role of glutamine anaplerosis flux in the survival and proliferation of clonal plasma cells in MM (Aim 2). Finally, it will determine if systemic biomarkers associated with glutamine anaplerosis are associated with the pathogenesis of MM (Aim 3). These studies will provide an opportunity to advance our understanding of the metabolic rewiring associated with the pathogenesis of MM and could allow us to better define the transition from MGUS to symptomatic MM. This would, in turn, facilitate the development of early diagnostic or preventative strategies. The expertise and resources of the members of the mentoring team, the availability of the monoclonal gammopathy biobank and metabolomics resources at Mayo Clinic, and the institutional commitment to the career development of Dr. Gonsalves ensures the viability of his training and execution of the proposed experiments.